Yazdi Misak, Ahnmark Andrea, William-Olsson Lena, Snaith Michael, Turner Nigel, Osla Fredrik, Wedin Marianne, Asztély Anna-Karin, Elmgren Anders, Bohlooly-Y Mohammad, Schreyer Sandra, Lindén Daniel
AstraZeneca Research & Development, Pepparedsleden 1, S-431 83 Mölndal, Sweden.
Biochem Biophys Res Commun. 2008 May 16;369(4):1065-70. doi: 10.1016/j.bbrc.2008.02.156. Epub 2008 Mar 11.
Glycerol-3-phosphate acyltransferase (GPAT) is involved in triacylglycerol (TAG) and phospholipid synthesis, catalyzing the first committed step. In order to further investigate the in vivo importance of the dominating mitochondrial variant, GPAT1, a novel GPAT1(-/-) mouse model was generated and studied. Female GPAT1(-/-) mice had reduced body weight-gain and adiposity when fed chow diet compared with littermate wild-type controls. Furthermore, GPAT1(-/-) females on chow diet showed decreased liver TAG content, plasma cholesterol and TAG levels and increased ex vivo liver fatty acid oxidation and plasma ketone bodies. However, these beneficial effects were abolished and the glucose tolerance tended to be impaired when GPAT1(-/-) females were fed a long-term high-fat diet (HFD). GPAT1-deficiency was not associated with altered whole body energy expenditure or respiratory exchange ratio. In addition, there were no changes in male GPAT1(-/-) mice fed either diet except for increased plasma ketone bodies on chow diet, indicating a gender-specific phenotype. Thus, GPAT1-deficiency does not protect against HFD-induced obesity, hepatic steatosis or whole body glucose intolerance.
甘油-3-磷酸酰基转移酶（GPAT）参与三酰甘油（TAG）和磷脂的合成，催化第一步关键反应。为了进一步研究主要的线粒体变体GPAT1在体内的重要性，构建并研究了一种新型的GPAT1基因敲除（-/-）小鼠模型。与同窝野生型对照相比，喂食普通饲料的雌性GPAT1基因敲除小鼠体重增加和肥胖程度降低。此外，喂食普通饲料的GPAT1基因敲除雌性小鼠肝脏TAG含量、血浆胆固醇和TAG水平降低，离体肝脏脂肪酸氧化和血浆酮体增加。然而，当GPAT1基因敲除雌性小鼠长期喂食高脂饮食（HFD）时，这些有益作用消失，葡萄糖耐量也趋于受损。GPAT1基因缺失与全身能量消耗或呼吸交换率的改变无关。此外，无论喂食哪种饲料，雄性GPAT1基因敲除小鼠均无变化，只是喂食普通饲料时血浆酮体增加，表明存在性别特异性表型。因此，GPAT1基因缺失并不能预防HFD诱导的肥胖、肝脂肪变性或全身葡萄糖不耐受。
